Elise's first film was Set It Off (1996), in which she played one of four women who resort to robbing a bank for money. Her big break came in 1997 when she was cast in the Family Channel original television movie The Ditchdigger's Daughters, based on the Pulitzer-prize nominated and critically acclaimed 1995 memoir The Ditchdigger's Daughters: A Black Family's Astonishing Success Story, written by Yvonne S. Thornton and Jo Coudert. She received critical acclaim for her role in this film, and in 1997, she was recognized as Best Supporting Actress in a Movie or Miniseries at the 19th annual CableACE Awards. A relative unknown at the time, she conveyed her anonymity upon receiving the award by saying: "Who is Kimberly Elise?"

Her performance helped her land a role the next year in Beloved alongside Oprah Winfrey and Danny Glover. She is often compared to a young Cicely Tyson, whom she resembles. In 2004, she appeared in Woman Thou Art Loosed portraying Michelle, an abused young woman who finally got the help she needed behind bars. This role won her a Black Reel award for Best Actress. She also appeared in John Q, The Manchurian Candidate and Diary of a Mad Black Woman (she won a NAACP Image Award for the latter). From 2005 to 2007, she was part of the main cast of the CBS crime drama Close to Home, playing theMarion County, Indiana (Indianapolis) prosecutor Maureen Scofield. Her character was killed off in the last episode of the series. The series was cancelled on May 2007.

She has since made a guest appearance on the situation comedy Girlfriends, in which she played an HIV-positive woman.Her most recent film role was in Tyler Perry's For Colored Girls (2010), as the battered wife Crystal. While the film itself received mixed to negative reviews, her performance was praised by many critics. One journalist described her as "the great lost Best Supporting Actress contender of the 2010 season". Since 2013 Kimberly is part of the cast of VH1's new series Hit The Floor.